Abstract
Antibody-derived chimeric antigen receptor (CAR) T cell therapy has achieved gratifying breakthrough in hematologic malignancies but has shown limited success in solid tumor immunotherapy. Monoclonal antibody, TAB004, specifically recognizes the aberrantly glycosylated tumor form of MUC1 (tMUC1) in all subtypes of breast cancer including 95% of triple-negative breast cancer (TNBC) while sparing recognition of normal tissue MUC1. We transduced human T cells with MUC28z, a chimeric antigen receptor comprising of the scFv of TAB004 coupled to CD28 and CD3ζ. MUC28z was well-expressed on the surface of engineered activated human T cells. MUC28z CAR T cells demonstrated significant target-specific cytotoxicity against a panel of human TNBC cells. Upon recognition of tMUC1 on TNBC cells, MUC28z CAR T cells increased production of Granzyme B, IFN-γ and other Th1 type cytokines and chemokines. A single dose of MUC28z CAR T cells significantly reduced TNBC tumor growth in a xenograft model. Thus, MUC28z CAR T cells have high therapeutic potential against tMUC1-positive TNBC tumors with minimal damage to normal breast epithelial cells.
Highlights
Triple-negative breast cancer (TNBC) is characterized for being negative in the expression of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), and accounts for ∼15% of invasive breast cancers [1, 2]
Selecting the optimal tumor-associated antigen (TAA) as a target for chimeric antigen receptor (CAR) T cells is critical toward successful adoptive T cell therapy
Due to the various challenges associated with adoptive immunotherapy and lack of antibodies that only recognize the tumor form but spares the normal form of Mucin1 glycoprotein (MUC1) [8], there are only limited preclinical studies on MUC1-specific CAR T therapy
Summary
Triple-negative breast cancer (TNBC) is characterized for being negative in the expression of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), and accounts for ∼15% of invasive breast cancers [1, 2]. Development of newer therapies, such as immunotherapy, for TNBC patients is warranted. Chimeric antigen receptors (CARs) are synthetic receptors that when engineered into T cells, they can redirect T cells to recognize a tumor-specific antigen, get activation to become cytolytic, and eventually lyse the tumor cells [4, 5]. The CAR T cell approach combines an extracellular single chain variable fragment (scFv) from an antibody that can recognize a tumor surface antigen, a transmembrane domain, and a T cell intracellular signaling domain into a fusion molecule for tumor cell lysis [6]. Despite its success in treating hematologic malignancies [2, 5, 7], CAR T cell immunotherapy remains a challenge for solid tumors due to lack of specific targetable cell
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